The invention relates to freeze-dried molded articles containing magnesium ascorbyl phosphate and alginate as well as optionally one or more active substances and/or auxiliary substances. Furthermore, the invention relates to methods for manufacturing these freeze-dried molded articles, the combination of such freeze-dried molded articles in kit-of-parts arrangements together with aqueous solutions, as well as the use of the freeze-dried molded articles and the kit-of-parts combinations for pharmaceutical and cosmetic application.
In the pharmaceutical and cosmetic application and administration of active ingredients and care substances or other active substances, the selection of provision of the suitable form of administration, in particular, plays a central role for the application of the active and/or care substances. Factors such as, e.g. reproducible and effective contents of active substances, a high degree of safety in storage and application, good and reproducible availability of the active substances after application are factors that must in this case be taken into account; optionally, a stabilization against degradation or decomposition of the active substances contained can be of importance, as well as the provision in a form of administration that is optimally adapted to the respective purpose of application. The choice of the suitable form of application in this case particularly depends on the type and place of application, the target group of end users and their special characteristics, the type and quantity of the dosage of the active substances or also, for example, the physical and biochemical characteristics of the active substances, in particular with regard to their biological availability and their systemic mode of action.
The stabilization and preservation of the preparations constitutes a particularly important aspect in the administration of active ingredients and substances or cosmetic care substances. Particularly long-lasting and stable form of administration are water-free or solid and dry preparations, which furthermore have particularly good storage and transport properties. Especially with regard to administration systems in dried or dry form, the central issue in the administration on and in the human body that arises is the dissolution or solubility of the form of administration and thus the release and availability of the active ingredients, care and active substances. The requirements with regard to the kind, rate and place of dissolution vary with the specific application, the substances to be applied as well as, if applicable, other factors to be taken into consideration.
In particular in the cosmetic application of active substances, forms of administration of particularly desired which makes the external administration of active ingredients, active and care substances on the skin and hair possible in an optimum manner, but the external application also plays a large role in the pharmaceutical application of active substances, in addition to the oral administration of active substances.
Water-free forms of administration are an appropriate means for the quick and specific application of active substances, in particular those that have a certain instability with regard to external factors, such as moisture, oxidation and temperature. Dry preparations that have a particularly fast and complete dissolution behavior are of particular interest. This is particularly relevant in making moisture-unstable active substances available, as well as generally in oral application of active substances that are to be absorbed, for example, via the oral mucosa, or for users who have problems swallowing tablets or capsules.
Other drawbacks of known dry forms of administration, such as powder mixtures, granules, tablets or capsules are in particular the frequently poor or slow solubility and thus the delayed active substance release, the high proportion of auxiliary and filler substances, which are inactive but necessary for processing, the regularly poor suitability for external application as well as an insufficient disability and thus safe handling or problems with application by the end user.
A suitable and known manner of providing active substances in a readily soluble, dry form of application or dosage is to disperse the active substances in a system of carrier substances and to subject this mixture to freeze drying. Mostly, such substances are selected as carrier substances that have a good dissolution or swelling behavior and which, through swelling, enable a good texture formation, so that the dissolved active substance system, or the active substance system dispersed in the swelling agent, can be used directly as a form of application. Such systems, because of their good solubility, are known and suitable for providing oral forms of application, as well as for producing cosmetic or pharmaceutical forms of administration for external application. In this case, there in a increasing interest in providing so-called single-unit forms of application which enable a simple and precise application of a dose of an active substance for the end user. Single-unit forms of application in this context are understood to be application systems, which in contrast to powders or granules contain the desired and required quantity of active substance per application unit in a single application unit, such as tablets or capsules, without, however, having the drawbacks of difficulties with regard to swallowing, poor solubility or lack of suitability for external application.
For both cosmetic and pharmaceutical application of single-application molded articles, relatively large molded articles of a uniform shape and size are preferred because in contrast to powders or small pellets and granules, they can be handled more easily by the end user, so that the intention is to provide molded articles of such a size that permit a single dosage form per application. Moreover, larger molded articles, which can, for example, be given a colored design, also leave a stronger aesthetic impression.
Increasingly, larger-format configurations of such single-unit forms of application stabilized by drying are becoming interesting for oral and/or external administration of active substances which are characterized by a particularly quick, reliable and complete dissolution behavior, if possible without any inhomogeneous, incompletely dissolved residues.
The dissolution behavior of a molded article is a complex function of physical/chemical parameters. The physical basis for the kinetic aspect of the hydration process is constituted by individual parameters, such as swelling capability of the carrier substances used, structural integrity of the molded article while swelling, pore size, capillary forces caused by the pore structure, components of the recipe altering surface tension, density of the molded article etc. Apart from pure “solubility”, or, in the case of polymer-based carrier substances, the “swelling capacity”, the mechanical stability of the molded article in this case plays a pivotal role. If the polymeric material swells too quickly, the molded article loses its physical integrity too quickly and collapses. The molded article melts while moisture is added, in most cases while forming “inner” areas with a lower moisture content that have not yet swelled.
If the stabilizing interactions within the material are too large, the material may swell while water is added, but then decomposes only under mechanical stress, such as by mechanical stirring, rubbing, squashing or massaging. A compromise, sufficient mechanical strength for compensating the weight increase while swelling with subsequent rapid hydration is very difficult to achieve.
Known rapidly soluble dosage forms, e.g. for oral application of active substances are produced by the companies R. P. Scherer and Cardinal Health under the brand name Zydis®, wherein the liquid active substance composition is filled into a blister pack and freeze-dried in the final packaging. This method is necessary because of the low mechanical stability of the readily soluble oral dosage forms that can be obtained thereby. The lack of mechanical stability, however, is disadvantageous with regard to the external application. Moreover, molded articles to be handled individually with sufficient mechanical stability for use as single-unit forms of application with a particularly rapid and complete dissolution behavior are obviously not available. Moreover, a method for freeze drying in blister packs is technically complex and cost-intensive, and the forms of administration that can be obtained thereby are limited to conventional blister packs with regard to their presentation and combination possibilities, which is undesirable in particular with regard to cosmetic applications.
Other rapidly soluble preparations that are also freeze-dried in blister packs because of a lack in mechanical stability are the subject matter of U.S. Pat. No. 4,758,0598 and U.S. Pat. No. 4,305,502.
DE 69727922 is distinct therefrom by producing oral, rapidly soluble forms of administration with a higher stability, which contain relatively high contents of fillers, such as, e.g., mannitol as well as binding agents, such as, e.g., alginate, and which are not obtainable by means of expensive and complicated freeze-drying methods. The oral dosage forms thus obtainable are characterized by a solubility of <15 seconds. However, it is not apparent from DE 69727922 that molded articles with a sufficient mechanical, which is required in particular for external application, are obtainable by means of the method described. Moreover, the issue of quick and complete dissolution without any mechanical influence and, in the process, without the formation of Inhomogeneous, non-swelled inner areas, is not broached. Since the dosage forms described in DE 69727922 are only intended for oral application, such a special dissolution behavior is not really relevant, because the actions of the tongue and the palate inevitably constitute a mechanical influence, which, if necessary, support non-uniformly dissolved areas in their continued dissolution. Other known methods for providing rapidly soluble forms of application of active substances that can be used as single-unit dosage forms with a certain size are described in U.S. Pat. No. 5,405,616 and DE 4201179. The carrier materials used therein preferably are based on proteins. The pellets are produced by dripping dispersions of the protein scaffold-forming agents and optionally cosmetic or pharmaceutical active substances into cryogenic inert liquids, preferably liquid nitrogen, and subsequently separating and freeze-drying the frozen pellets. However, the presence of protein scaffold-forming agents, in particular of collagen or collagen derivatives, is necessary in order to form pellets under these conditions, because only the aforementioned protein scaffold-forming agents are able to form stable pellets under these conditions. However, proteinogenic carrier materials are unsuitable for achieving a particularly quick and complete dissolution behavior without any residues of swelled areas and, in particular, without any mechanical influence, as is desired in this case, because of the high requirements with regard to the intramolecular stabilization of the composition in the dripping method used.
Similar problems result from the method for producing porous galenic particles described in U.S. Pat. No. 5,843,347, which are supposed to be obtained in sizes of up to 5 mm, according to the description. In the method used herein, a mixture of the active substances is extruded in a matrix and cut into particles with the desired size, which subsequently form the porous molded articles by freeze drying. However, the exemplary embodiments merely show that so-called microspheres with diameters of up to a maximum of 1.5 mm can be obtained. This can be ascribed to the use according to the invention of an extrusion and cutting method that requires a certain mechanical stability of the extruded mass. This can generally be obtained by a relatively high content of scaffold-forming polymers or carrier substances and stabilizers or fillers. However, if only small amounts of stabilizing carrier or auxiliary substances are used as compared with the content of active substances, then very small-format microspheres can be obtained, as is shown in this document.
Another method that provides the production of readily soluble molded articles loaded with active substances is the subject matter of WO 05/073296 and WO 04/011537, with neither document giving any specific statements with regard to the kind or, in particular, rate of the dissolution. Especially the particularly rapid and residue-free dissolution without mechanical influence is not mentioned.
A rapidly soluble large-format molded article that is suitable for the external administration of active substances is the subject matter of DE 10248314, which was also published as WO 2004/035023. The forms of application that can be obtained by the method described therein are large-formal molded articles of a regular shape loaded with active substances, which articles can be obtained by a freeze-drying method of an active substance-scaffold-forming agent mixture poured into molds. The molded articles that can be obtained according to the described method are characterized by good mechanical stability and a high dissolution rate of <4 minutes, with the latter being fundamentally dependent, however, on the respective content of scaffold-forming-agents. Dissolution rates of up to <20 seconds are described, with such a rapid dissolution only being achieved by means of applying mechanical forces, e.g. in the form of stirring, rubbing or massaging.
Thus, in order to be able to obtain dosage forms with even more rapid and better solubility with complete and residue-free decomposition, which decompose homogeneously and uniformly, in particular, without any mechanical influence, and which do not leave behind any swelled inhomogeneous areas in the process, and which are thus particularly suitable for the administration of cosmetic and pharmaceutical active ingredients, active and care substances, no suitable methods and compositions are so far known from the prior art.